At the present time the use of inactivated influenza A virus vaccine is not fully satisfactory. Development of live attenuated influenza A virus vaccines promises to have significant advantages in that respiratory infections with such attenuated viruses will stimulate more effective and durable immunity than that which occurs with parenteral inactivated vaccines. Recently temperature sensitive (ts) mutants of influenza A virus have been developed and evaluated for level of attenuation and immunogenicity in humans. (Tolpin M. D., M. L. Clements, M. M. Levine, R. E. Black, A. J. Saah, W. C. Anthony, L. Cisneros, R. M. Chanock and B. R. Murphy. 1982. Evaluation of a phenotypic revertant of the A/Alaska/77-ts-1A2 reassortant virus in hamsters and in seronegative adult volunteers: Further evidence that the temperature-sensitive phenotype is responsible for attenuation of ts-1A2 reassortant viruses. Infection and Immunity 36: 645-650.) Although some strains afford protection, the clinical studies also indicate illness and shedding of the virus from the vaccinated volunteers. (Cate, T. R. and Couch, R. B. 1982. Live influenza A/Victoria/75 (H3N2) virus vaccines: Reactogenicity, immunogenicity, and protection against wild-type virus challenge. Infection and Immunity 38: 141-146.) Recent reports also indicate that some of the temperature sensitive reassortment viruses (A/Udorn/72-ts-1A2 and A/Alaska/77-ts1A2) undergo progressive loss of temperature sensitivity (Murphy, B. R., L. J. Markoff, N. T. Hosier, J. G. Massicot and R. M. Chanock. 1982. Production and level of genetic stability of an influenza A virus temperature-sensitive mutant containing two genes with ts mutations. Infection and Immunity 37: 235-242. and Tolpin et al. supra) The loss of the ts phenotype is accompanied by the restoration of virulence.
One object of this invention is to provide a virus vaccine which is more effective and durable than previously described vaccines.
Other objects and advantages of this invention will be apparent from the description and claims which follow taken together with the appended tables and charts.